RESUMEN

This study aims to assess the potential bioactivity of newly designed benzodiazepine-1,2,3-triazole derivatives using in-silico methodologies, with a primary focus on elucidating their inhibitory interactions with the butyrylcholinesterase (BuChE) enzyme, which is implicated in Alzheimer's disease. We employed multiple linear regression (MLR) methods to conduct a quantitative structure-activity relationship (QSAR) analysis on a collection of 31 benzodiazepine-1,2,3-triazole derivatives, with the goal of investigating, assessing, and predicting their activities, as well as designing novel compounds. This approach yielded highly accurate results, with coefficients of determination (R²) of 0.77 and 0.81 for the training and test datasets, respectively. Additionally, the optimized compounds were subjected to an Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis, demonstrating their potential as non-hepatotoxic agents with enhanced absorption and blood-brain barrier permeability. To further validate these findings, the most favorable docking conformations were analyzed using molecular dynamics (MD) simulations with GROMACS software, predicting the stability of the formed complexes. These simulations underscored the critical role of hydrogen bonds in stabilizing the compounds at the BuChE receptor binding site. The results hold great promise for the development of innovative benzodiazepine-1,2,3-triazole derivatives as effective BuChE inhibitors, potentially leading to therapeutic interventions for Alzheimer's disease.

RESUMEN

In the current work, computational methods were used to investigate new isoxazole derivatives that could be used as tubulin inhibitors. The study aims to develop a reliable quantitative structure-activity relationship (QSAR) model, following the criteria set by Golbraikh, Tropsha, and Roy. As a result, seven candidate compounds were developed, all having higher activity than the well-established anticancer agent Cisplatin (Cisp). According to the ADMETox in silico test, the candidates Pr4, Pr5, and P6 can be toxic. As a result, we have chosen to focus our study on compounds Pr1, Pr2, and Pr3. Molecular docking analysis revealed that drug candidate Pr2 exhibits the highest stability within the oxidized quinone reductase 2 (PDB ID: 4zvm), target receptor (ΔG(Pr2) = ΔG(Pr3) = -10.4 < ΔG(Pr1) = -10.0 < ΔG(Cisp) = -7.3 kcal/mol). This finding aligns with the activity predictions made by the QSAR model. Furthermore, molecular dynamics simulations of the Pr2-4zvm complex over 100 ns confirm the ligand's robust stability within the receptor's active site, supporting the results obtained from molecular docking and the QSAR model predictions. The CaverDock software was utilized to identify the tunnels likely to be followed by ligands moving from the active site to the receptor surface. This analysis also helped in determining the biological efficacy of the target compounds. The results indicated that the Pr2 compound is more effective than the others. Finally, the computer-assisted retrosynthesis process of two high confidence sequences was used to synthesize drug candidates.Communicated by Ramaswamy H. Sarma.

3D-QSAR methods were used to design eight new compounds and anti-tubulin agents.3D-QSAR models were validated by Golbraikh­Tropsha and Roy methods.The toxicity and pharmacokinetics of the proposed compounds were identified by the Lipinski rule of five, Veber rules, and ADMETox.Pr2 and Pr3 had a reasonable affinity to the receptor protein (ID PDB: 4zvm) based on molecular docking, reactivity indices, and molecular dynamics simulation.Metadynamics was used to study ligand transport in the receptor (ID PDB:3zvm).

RESUMEN

It is challenging to model the toxicity of nitroaromatic compounds due to limited experimental data. Nitrobenzene derivatives are commonly used in industry and can lead to environmental contamination. Extensive research, including several QSPR studies, has been conducted to understand their toxicity. Predictive QSPR models can help improve chemical safety, but their limitations must be considered, and the molecular factors affecting toxicity should be carefully investigated. The latest QSPR methods, molecular modeling techniques, machine learning algorithms, and computational chemistry tools are essential for developing accurate and robust models. In this work, we used these methods to study a series of fifty compounds derived from nitrobenzene. The Monte Carlo approach was used for QSPR modeling by applying the SMILES molecular structure representation and optimal molecular descriptors. The correlation ideality index (CII) and correlation contradiction index (CCI) were further introduced as validation parameters to estimate the developed models' predictive ability. The statistical quality of the CII models was better than those without CII. The best QSPR model with the following statistical parameters (Split-3): (R2 = 0.968, CCC = 0.984, IIC = 0.861, CII = 0.979, Q2 = 0.954, QF12 = 0.946, QF22 = 0.938, QF32 = 0.947, Rm2 = 0.878, RMSE = 0.187, MAE = 0.151, FTraining = 390, FInvisible = 218, FCalibration = 240, RTest2 = 0.905) was selected to generate the studied promoters with increasing and decreasing activity.

Asunto(s)

RESUMEN

CONTEXT: The regioselectivity and diastereoselectivity of the 1,3-dipolar cycloaddition reaction between azomethine ylides and acrolein were investigated. The DFT studies revealed that the favored pathway leads to the formation of cis-cycloadduct pyrrolidine and these computational findings align with experimental observations. The cis-cycloadduct pyrrolidine product serves as an advanced intermediate in the synthesis of a hepatitis C virus inhibitor. For this, the antiviral activity of cis-cycloadduct pyrrolidine against cyclophilin A, the co-factor responsible for hepatitis C virus, was also evaluated through molecular docking simulations which revealed intriguing interactions and a high C-score, which were further confirmed by molecular dynamics simulations, demonstrating stability over a 100-ns simulation period. Furthermore, the cis-cycloadduct pyrrolidine exhibits favorable drug-like properties and a better ADMET profile compared to hepatitis C virus inhibitor. METHODS: Chemical reactivity studies were performed using DFT method by the functional B3LYP at 6-31G (d, p) computational level by GAUSSIAN 16 program. Frontal molecular orbitals theory used to investigate HOMO/LUMO interactions between azomethine ylides and acrolein. Findings of this approach were confirmed by global reactivity indices and electron displacement was investigated based on Fukui functions. Furthermore, the activation energies were determined after frequency calculations using TS Berny algorithm and transition states were confirmed by the presence of a single imaginary frequency. Moreover, antiviral activity of cis-cycloadduct was explored through molecular docking using Surflex-Dock suite SYBYL X 2.0, and molecular dynamics simulation using GROMACS program. Finally, drug-like properties were investigated with SwissADME and ADMETlab 2.0.

Asunto(s)

RESUMEN

Cancer is the uncontrolled spread of abnormal cells that results in abnormal tissue growth in the affected organ. One of the most important organs is exposed to the growth of colon cancer cells, which start in the large intestine (colon) or the rectum. Several therapeutic protocols were used to treat different kinds of cancer. Recently, several studies have targeted tubulin and microtubules due to their remarkable prefoliation. Also, recent research shows that quinoline compounds have significant efficacy against human colorectal cancer. So, the present work investigated the potential of thirty quinoline compounds as tubulin inhibitors using computational methods. A 3D-QSAR approach using two contours (CoMFA and CoMSIA), molecular docking simulation to determine the binding type of the complexes (ligand-receptor), molecular dynamics simulation and identifying pharmacokinetic characteristics were used to design molecules. For all compounds designed (T1-5), molecular docking was used to compare the stability by type of binding. The ADMET has been utilized for molecules with good stability in molecular docking (T1-3); these compounds have good medicinal characteristics. Furthermore, a molecular dynamics simulation (MD) at 100 ns was performed to confirm the stability of the T1-3 compounds; the molecules (T1-3) remained the most stable throughout the simulation. The compounds T1, T2 and T3 are the best-designed drugs for colorectal carcinoma treatments.Communicated by Ramaswamy H. Sarma.

Asunto(s)

RESUMEN

Pancreatic cancer, known as the "silent killer," poses a daunting challenge in cancer therapy. The dysregulation of the PI3Kα signaling pathway in pancreatic cancer has attracted considerable interest as a promising target for therapeutic intervention. In this regard, the use of curcumin derivatives as inhibitors of PI3Kα has emerged, providing a novel and promising avenue for developing effective treatments for this devastating disease. Computational approaches were employed to explore this potential and investigate 58 curcumin derivatives with cytotoxic activity against the Panc-1 cell line. Our approach involved ligand-based pharmacophore modeling and atom-based 3D-QSAR analysis. The resulting QSAR model derived from the best-fitted pharmacophore hypothesis (AAHRR_1) demonstrated remarkable performance with high correlation coefficients (R2) of 0.990 for the training set and 0.977 for the test set. The cross-validation coefficient (Q2) of 0.971 also validated the model's predictive power. Tropsha's recommended criteria, including the Y-randomization test, were employed to ensure its reliability. Furthermore, an enrichment study was conducted to evaluate the model's performance in identifying active compounds. AAHRR_1 was used to screen a curated PubChem database of curcumin-related compounds. Two molecules (CID156189304 and CID154728220) exhibited promising pharmacokinetic properties and higher docking scores than Alpelisib, warranting further investigation. Extensive molecular dynamics simulations provided crucial insights into the conformational dynamics within the binding site, validating their stability and behavior. These findings contribute to our understanding of the potential therapeutic effectiveness of these compounds as PI3Kα inhibitors in pancreatic cancer.Communicated by Ramaswamy H. Sarma.

RESUMEN

The efficacy of 40 synthesized variants of 3,5-diaryl-1H-pyrazole and spiropyrazoline' derivatives as acetylcholinesterase inhibitors is verified using a quantitative three-dimensional structure-activity relationship (3D-QSAR) by comparative molecular field analysis (CoMFA) and molecular similarity index analysis (CoMSIA) models. In this research, different field models proved that CoMSIA/SE model is the best model with high predictive power compared to several models (Qved2 = O.65; R2 = 0.980; R2test = 0.727). Also, contour maps produced by CoMSIA/SE model have been employed to prove the key structural needs of the activity. Consequently, six new compounds have been generated. Among these compounds, M4 and M5 were the most active but remained toxic and had poor absorption capacities. While the M1, M2, M3 and M6 remained highly active while respecting ADMET's characteristics. Molecular docking results showed compound M2 better with acetylcholinesterase than compound 22. The interactions are classical hydrogen bonding with residues TYR:124, TYR:72, and SER:293, which play a critical role in the biological activity as AChE inhibitors. MD results confirmed the docking results and showed that compound M2 had satisfactory stability with (ΔGbinding = -151.225 KJ/mol) in the active site of AChE receptor compared with compound 22 (ΔGbinding = -133.375 KJ/mol). In addition, both compounds had good stability regarding RMSD, Rg, and RMSF. The previous results show that the newly designed compound M2 is more active in the active site of AChE receptor than compound 22.Communicated by Ramaswamy H. Sarma.

RESUMEN

BRAF inhibitors are known to be an effective therapeutic target for treating melanoma and other types of cancer. Using 3D-QSAR, molecular docking, and MD simulations, this study evaluated various imidazo[2,1-b]oxazole derivatives that function as mutant BRAF kinase inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were used to create the 3D-QSAR models. CoMSIA/SEHA model has solid predictive power across several models (Q2 = 0.578; R2 = 0.828; R2pred = 0.74) and is the best model according to the numerous field models generated. The created model's predictive power was evaluated through external validation using a test set. CoMSIA/SEHA contour maps collect information that can be used to identify critical regions with solid anticancer activity. We developed four inhibitors with high predicted activity due to these observations. ADMET prediction was used to assess the toxicity of the proposed imidazo[2,1-b]oxazole compounds. The predictive molecules (T1-T4) demonstrated good ADMET properties, excluding the toxic active compounds 11r from the database. Molecular docking was also used to determine the patterns and modes of interactions between imidazo[2,1-b]oxazole ligands and receptors, which revealed that the proposed imidazo[2,1-b]oxazole scaffold was stable in the receptor's active site (PDB code: 4G9C). The suggested compounds (T1-T4) were subjected to molecular dynamics simulations lasting 100 ns to determine their binding free energies. The results showed that T2 had a more favorable binding free energy (-149.552 kJ/mol) than T1 (-112.556 kJ/mol), T3 (-115.503 kJ/mol), and T4 (-102.553 kJ/mol). The results suggest that the imidazo[2,1-b]oxazole compounds investigated in this study have potential as inhibitors of BRAF kinase and could be further developed as anticancer drugs. Highlights22 imidazo[2,1-b]oxazole compounds were subjected to research on three-dimensional quantitative conformational relationships.Using contour maps from 3D-QSAR models as a guide was used to figure out the areas and strategies for structural optimization.Combined molecular docking, molecular dynamics simulations, and binding free energy calculations to verify the inhibitor activity of the proposed 22 imidazo[2,1-b]oxazole compounds.Four potential B-RAF Kinase inhibitors were discovered, providing theoretical clues for developing a highly anticancer agent.Communicated by Ramaswamy H. Sarma.

RESUMEN

Because of the increasing scarcity of fossil fuels and the growing need for energy, it has become necessary to research new renewable energy resources. In this study, five new high-performance materials (TP-FA1F-TP - TP-FA5F-TP) of the D-π-A-π-D configuration based on triphenylamine (TPA) were theoretically investigated by applying DFT and TD-DFT methods for future application as heterojunction organic solar cells (BHJ). The influence of the modification of the acceptor (A) of the parent molecule TP-FTzF-TP on the structural, electronic, photovoltaic and optical properties of the TP-FA1F-TP - TP-FA5F-TP organic molecules was investigated in detail. TP-FA1F-TP - TP-FA5F-TP showed Egap in the interval of 1.44-2.01 eV with λabs in the range of 536-774 nm, open-circuit voltage (Voc) values varied between 0.3 and 0.56 V and power conversion efficiencies (PCE) ranging from (3-6) %. Our results also show that the donor molecules suggested in this research exhibit an improved performance compared to the recently synthesized TP-FTzF-TP, such as a lowest HOMO energy, a smaller Egap, and a greater absorption spectrum, and can lead to higher performance. Indeed, this theoretical research could lead to the future synthesis of better compounds as active substances used in BHJ.

Asunto(s)

RESUMEN

Fluconazole and Voriconazole are individual antifungal inhibitors broadly adopted for treating fungal infections, including Candida Albicans. Unfortunately, these medicines clinically used have significant side effects. Consequently, the improvement of safer and better therapy became more indispensable. In this study, a set of 27 1,2,4-triazole compounds have been tested as potential Candida Albicans inhibitors by using different theoretical methods. The created comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour maps significantly impacted the development of novel Candida Albicans inhibitors with valuable activities. The mode of interactions between the 1,2,4-triazole inhibitors and the targeted receptor was studied by molecular docking simulation. The proposed new molecule P1 showed satisfied stability in the active pocket of the targeted receptor compared to the more active molecule in the dataset compared to Fluconazole medication. Meanwhile, the binding energy obtained by molecular docking for molecule P1 is - 9.3 kcal/mol compared with - 6.7 kcal/mol for Fluconazole medication. Also, MM/GBSA value obtained by molecular dynamics simulations at 100 ns for molecule P1 is - 33.34 kcal/mol compared with - 15.85 kcal/mol for Fluconazole medication. In addition, molecule P1 showed good oral bioavailability and was non-toxic according to ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Therefore, the results indicated compound P1 might be a future inhibitor of Candida Albicans infection.

Asunto(s)

RESUMEN

Plasmepsin II is a key enzyme in the life cycle of the Plasmodium falciparum parasite responsible for malaria, a disease that is causing deaths on a worldwide scale. Recently, plasmepsin II enzyme has gained much importance as an attractive drug target for the investigation of antimalarial drugs. In this sense, structure-based virtual screening have been utilized as tools in the process of discovering novel natural compounds based on quinoline as potential plasmepsin II inhibitors. Among the 58 quinoline derivatives isolated from different plants was screened by utilizing docking molecular, ADMET approaches, molecular dynamics simulation and MM-PBSA binding free energy. The first step in this work is building the 3 D structures of the plasmepsin II enzyme by using the SWISS-MODEL software. The optimized structures were subjected to virtual screening by Autodock Vina, an entity implicated in PyRx software. 21 were selected based on their binding affinity. The binding modes and interactions of the top-21 selected compounds were evaluated using AutoDock 4.2. Then, the pharmacokinetic proprieties and toxicity of these compounds were evaluated using ADMET analysis. Ten compounds were predicted to have ADMET characteristics with no side effects. Compounds M49 and M53 were found to be potential inhibitors. The stability of the selected two compounds was confirmed by MD simulation and MM/PBSA calculation during 200 ns. This study can be used to predict and to design new antimalarial drugs.Communicated by Ramaswamy H. Sarma.

Asunto(s)

RESUMEN

Global energy consumption has increased due to population growth and economic development. Solar energy is one of the most important renewable energy sources for human consumption. In this research, four novel organic dyes (D2-D5) of the D-A-π-A structure based on triphenylamine (TPA) were studied theoretically using DFT and TD-DFT techniques for future usage as dye-sensitized solar cells (DSSCs). The effects of modifying the π-spacer of the reference molecule D1 on the structural, electronic, photovoltaic, and optical characteristics of the D2-D5 dyes were studied in detail. D2-D5 exhibited band gaps (E gap) in the range from 1.89 to 2.10 eV with λ abs in the range of 508 to 563 nm. The results obtained show that modifying the π-spacer of the dye D1 increased its hole injection and reinforced the intramolecular charge-transfer (ICT) impact, which resulted in a red-shifted ICT absorption with a greater molar extinction coefficient. The theoretically calculated open-circuit voltage (V oc) values ranged from 0.69 to 1.06 eV, while the light-harvesting efficiency (LHE) values varied from 0.95 to 0.99. Indeed, this theoretical research could guide chemists to synthesize effective dyes for DSSCs.

RESUMEN

SARS-COV-2 virus causes (COVID-19) disease; it has become a global pandemic since 2019 and has negatively affected all aspects of human life. Scientists have made great efforts to find a reliable cure, vaccine, or treatment for this emerging disease. Efforts have been directed towards using medicinal plants as alternative medicines, as the active chemical compounds in them have been discovered as potential antiviral or anti-inflammatory agents. In this research, the potential of Saussurea costus (S. Costus) or QUST Al Hindi chemical consistent as potential antiviral agents was investigated by using computational methods such as Reverse Docking, ADMET, and Molecular Dynamics with different proteases COVID-19 such as PDB: 2GZ9; 6LU7; 7AOL, 6Y2E, 6Y84. The results of Reverse Docking the complex between 6LU7 proteases and Cynaropicrin compound being the best complex, as the same result, is achieved by molecular dynamics. Also, the toxicity testing result from ADMET method proved that the complex is the least toxic and the safest possible drug. In addition, 6LU7-Cynaropicrin complex obeyed Lipinski rule; it formed ≤5 H-bond donors and ≤10 H bond acceptors, MW < 500 Daltons, and octanol/water partition coefficient <5.

Asunto(s)

RESUMEN

Introduction: The new species of coronaviruses (CoVs), SARS-CoV-2, was reported as responsible for an outbreak of respiratory disease. Scientists and researchers are endeavoring to develop new approaches for the effective treatment against of the COVID-19 disease. There are no finally targeted antiviral agents able to inhibit the SARS-CoV-2 at present. Therefore, it is of interest to investigate the potential uses of levamisole derivatives, which are reported to be antiviral agents targeting the influenza virus. Methods: In the present study, 12 selected levamisole derivatives containing imidazo[2,1-b]thiazole were subjected to molecular docking in order to explore the binding mechanisms between these derivatives and the SARS-CoV-2 Mpro (PDB: 7BQY). The levamisole derivatives were evaluated for in silico ADMET properties for wet-lab applicability. Further, the stability of the best-docked complex was checked using molecular dynamics (MD) simulation at 20 ns. Results: Levamisole derivatives and especially molecule N°6 showed more promising docking results, presenting favorable binding interactions as well as better docking energy compared to chloroquine and mefloquine. The results of ADMET prediction and MD simulation support the potential of the molecule N°6 to be further developed as a novel inhibitor able to stop the newly emerged SARS-CoV-2. Conclusion: This research provided an effective first line in the rapid discovery of drug leads against the novel CoV (SARS-CoV-2).

RESUMEN

COVID-19 is a new infectious disease caused by SARS-COV-2 virus of the coronavirus Family. The identification of drugs against this serious infection is a significant requirement due to the rapid rise in the positive cases and deaths around the world. With this concept, a molecular docking analysis for vitamins and their derivatives (28 molecules) with the active site of SARS-CoV-2 main protease was carried out. The results of molecular docking indicate that the structures with best binding energy in the binding site of the studied enzyme (lowest energy level) are observed for the compounds; Folacin, Riboflavin, and Phylloquinone oxide (Vitamin K1 oxide). A Molecular Dynamic simulation was carried out to study the binding stability for the selected vitamins with the active site of SARS-CoV-2 main protease enzyme. Molecular Dynamic shows that Phylloquinone oxide and Folacin are quite unstable in binding to SARS-CoV-2 main protease, while the Riboflavin is comparatively rigid. The higher fluctuations in Phylloquinone oxide and Folacin indicate that they may not fit very well into the binding site. As expected, the Phylloquinone oxide exhibits small number of H-bonds with protein and Folacin does not form a good interaction with protein. Riboflavin exhibits the highest number of Hydrogen bonds and forms consistent interactions with protein. Additionally, this molecule respect the conditions mentioned in Lipinski's rule and have acceptable ADMET proprieties which indicates that Riboflavin (Vitamin B2) could be interesting for the antiviral treatment of COVID-19.

RESUMEN

Covid-19 is an emerging infectious disease caused by coronavirus SARS-CoV-2. Due to the rapid rise in deaths resulted from this infection all around the world, the identification of drugs against this new coronavirus is an important requirement. Among the drugs that can fight this type of infection; natural products are substances that serve as sources of beneficial chemical molecules for the development of effective therapies. In this study, Camphor, Artemisinin and 14 Sumac phytochemicals were docked in the active site of SARS-CoV-2 main protease (PDB code: 6LU7). We have also performed molecular dynamic simulation at 100 ns with MM-GBSA/PBSA analysis for the structures with the best affinity in the binding site of the studied enzyme (Hinokiflavone and Myricetin) after docking calculations to consider parameters like RMSD, covariance, PCA, radius of gyration, potential energy, temperature and pressure. The result indicates that Hinokiflavone and Myricetin are the structures with best affinity and stability in the binding site of the studied enzyme and they respect the conditions mentioned in Lipinski's rule and have acceptable ADMET proprieties; so, these compounds have important pharmacokinetic properties and bioavailability, and they could have more potent antiviral treatment of COVID-19 than the other studied compounds.

Asunto(s)